Reactive oxygen species stabilize hypoxia-inducible factor-1 alpha protein and stimulate transcriptional activity via AMP-activated protein kinase in DU145 human prostate cancer cells
Reactive oxygen species stabilize hypoxia-inducible factor-1 alpha protein and stimulate transcriptional activity via AMP-activated protein kinase in DU145 human prostate cancer cells
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DOI：
10.1093/carcin/bgn032
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发表时间：
2008-04-01
期刊：
影响因子：
4.7
通讯作者：
Ha, Joohun
中科院分区：
文献类型：
--
作者：
Jung, Seung-Nam;Yang, Woo Kyeom;Ha, Joohun
缺氧诱导因子（Hypoxia-inducible factor，HIF-1）在细胞对缺氧条件的适应性反应中起重要作用，而缺氧条件与肿瘤等病理生理条件密切相关。尽管活性氧（reactive oxygen species，ROS）参与了低氧和非低氧条件下HIF-1诱导表达的调控，但ROS的作用仍存在争议，其调控HIF-1表达的机制至今尚未完全阐明。在这里，我们研究的生化机制，为ROS诱导的HIF-1通过揭示一个新的作用，腺苷一磷酸活化蛋白激酶（AMPK）和上游信号成分。AMPK在腺苷三磷酸缺乏的条件下作为能量传感器发挥重要作用。在这里，我们报告，ROS诱导的直接应用H2 O2和甲萘醌DU 145人前列腺癌导致HIF-1 α蛋白的积累，衰减其降解和激活其转录活性的AMPK依赖性的方式。相比之下，AMPK仅是缺氧条件下HIF-1转录活性所需的，这揭示了AMPK在这两种刺激中的不同作用。此外，我们的数据显示，AMPK的抑制增强了ROS条件下HIF-1 α的泛素化。最后，我们表明，HIF-1的调节AMPK在ROS的反应是在c-Jun N-末端激酶和Janus激酶2途径的控制下。总的来说，我们的研究结果确定AMPK作为一个关键的决定因素HIF-1的功能，在响应ROS和其可能的作用，在复杂的HIF-1的调节机制。
Hypoxia-inducible factor (HIF-1) plays a central role in the cellular adaptive response to hypoxic conditions, which are closely related to pathophysiological conditions, such as cancer. Although reactive oxygen species (ROS) have been implicated in the regulation of hypoxic and non-hypoxic induction of HIF-1 under various conditions, the role of ROS is quite controversial, and the mechanism underlying the HIF-1 regulation by ROS is not completely understood yet. Here, we investigated the biochemical mechanism for the ROS-induced HIF-1 by revealing a novel role of adenosine monophosphate-activated protein kinase (AMPK) and the upstream signal components. AMPK plays an essential role as energy-sensor under adenosine triphosphate-deprived conditions. Here we report that ROS induced by a direct application of H2O2 and menadione to DU145 human prostate carcinoma resulted in accumulation of HIF-1 alpha protein by attenuation of its degradation and activation of its transcriptional activity in an AMPK-dependent manner. By way of contrast, AMPK was required only for the transcriptional activity of HIF-1 under hypoxic condition, revealing a differential role of AMPK in these two stimuli. Furthermore, our data show that inhibition of AMPK enhances HIF-1 alpha ubiquitination under ROS condition. Finally, we show that the regulation of HIF-1 by AMPK in response to ROS is under the control of c-Jun N-terminal kinase and Janus kinase 2 pathways. Collectively, our findings identify AMPK as a key determinant of HIF-1 functions in response to ROS and its possible role in the sophisticated HIF-1 regulatory mechanisms.